Pharmaceutical combination preparation containing glycyrrhizine, zinc, and a compound comprising a thiol group or a group that is metabolized thereto

ABSTRACT

The invention relates to the application of a combination including all forms of zinc at least one for the orally applied combination of a free thiol group or a group that is metabolized to a free thiol in a mammal, and as a the only pure plant part, glycyrrhicinic acid or the substance from succus liquiritiae for the production of a medication to fight acute or chronic viral infections.

The invention consists of a pharmaceutical or Nutrient combination preparation, of glycyrrhicinic acid, zinc and an orally acceptable connection to a free thiol group or a group that can be metabolized to a thiol group in a mammal's body. The invention further relates to a use for application for fighting viral infections especially Flu types of viruses.

Glycyrrhicinic acid (or glycyrrhicin) is an integral part of the root of Glycyrrhizia glabra LINNÉ (commonly called Licorice) with the following structural formula:

The natural, unpeeled dried root of glycyrrhiqia glabra is known as licorice root, and used as a medication in the natural healing arts. Liquid and solid forms for oral intake are known as succus liquiritiae. Licorice is made of such succus liquiritiae with a concentration of glycyrrhicinic acid of more than 1%. In Natural medicine, licorice root is used for catarrh, in the upper airways, and ulcers in the stomach and duodenum. In catarrh the expectorant, mucolytic and anti-inflammatory actions of the medication are most known.

In animal studies, glycyrrhicinic acid has shown an interferon inducing effect, connected to an antiviral effect. It also shall have a direct antiviral effect. Zinc is also known as a trace element that is imperative for the Immune system. In cases of viral infection, when zinc is taken, it increases the interferon activity to a multiple. In addition, zinc has a direct antiviral activity on the viral replication.

Thiol containing substances have many therapeutic acitivities. In connection to this invention, it is especially meaningful that thiol groups increase the number of antiviral functioning lymphocytes, e.g. the Th-1 lymphocytes and natural killer cells which are the sources for interferon especially interferon alpha and interferon gamma. The increase in the number of functioning competent immune cells is the result of the binding of the thiol group to nitric oxide. The concentration of nitric oxide (NO) is elevated in viral infections and responsible for the immobilization of the antiviral lymphocytes, which weakens the natural endogenous defense against viral infections.

In Japan there is a combination preparation of glycyrrhicinic acid, glycine and cysteine on the market to treat chronic viral hepatitis and post hepatic liver cirrhosis. The purpose of the invention is to create a synergistic antiviral activity that is greater than one would expect from an application of the individual components.

This purpose is met through the composition according to claim 1 and the usage according to claim 8.

The inventor surprisingly discovered the combination of glycyrrhicinic acid, zinc and a thiol containing group, or metabolized to a thiol containing group had an astounding antiviral activity.

The combination of substances can be in the form of three separate preparations, in a single package. It could also be any two of the substances worked into one combined substance. Further all three substances could be formed together into one combination substance.

Glycyrrhicinic acid is preferentially applied in the invention in the form of succus liquiritiae. Succus liquiritiae can be a liquid or a dried powder, which as mentioned above is obtained from the licorice root. A preferable succus liquiritiae liquid contains 5% glycyrrhicinic acid (50 mg/ml)

The oral dose of glycyrrhicinic acid is preferably 1500 mg to 2000 mg per day for adults. It is preferred to be given in two or three doses per day, especially preferred in three doses.

Zinc can be used in all typical pharmaceutical acceptable forms, including zinc orotate, zinc aspartate, zinc histidine, zinc sulfate, for the combination preparation according to the invention. The preferred oral dose for adults is 75 mg to 150 mg per day (referring to the element zinc). The daily dosage of zinc is also preferred to be portioned, e.g. three times a day.

The oral application of a free thiol group or a group that is metabolized to a free thiol group in mammals is chosen preferred from N-acetylcysteine, Methionine, Cysteine, allylcysteine, alpha liponic acid and Sulfur. Especially preferred is N-acetylcysteine, as this has also a mucolytic activity. All available preparations presently on the market are suitable including but not exclusively, ACC® from Hexal, Fluimucil® from Zambon etc.

This group of thiol containing substances is preferred at the doses of 1200 mg to 2400 mg for adults preferentially applied in divided doses per day, eg. three divided doses.

The daily doses of the individual substances for children is preferentially half of the adult doses.

The inventions combination preparation may contain additional pharmaceutical substances eg. paracetamol or acetyl salicylic acid.

The active substances of the inventions combination preparation is preferentially for oral application, although a parenteral, topical, intranasal, intravaginal and rectal application is not ruled out. Oral application forms include tablet, capsule, pill, buccal tablet, elixir, suspensions, syrups and similar forms. These application forms can include appropriate carriers eg dicalsium phosphate, binders such as gums, including gum arabicum, corn starch, or gelatine, breakdown products such as corn starch, potato starch, and Alginin acid, lubricants, such as magnesium stearate, sweetening substances, taste enhancers and all other commonly used enhancing and support subtances used in the pharmaceutical industry.

The invention combination preparation is for fighting acute and chronic, preferentially acute, virus infections for example, but not limited to corona viruses, rhino viruses, coxsackie viruses, Influenza A- and B-viruses, Herpses viruses, cytomegaloviruses, hepatitis A-, B- and C-viruses, Epstein-Barr-virus, and other viruses causing colds and all flu infections. This is especially applicable to infections of the upper respiratory tract.

It was surprisingly found that the combination preparation of the above three substances had an astounding synergistic activity.

In clinical studies each single substance was tested in flu symptoms (colds, flu, viral infection of the upper respiratory tract) whose duration without treatment normal lasted 7 days.

The results obtained were:

a) Zinc as a single treatment:

-   -   125mg per day, divided in three doses:

Slight lessoning of the duration of the illness to an average of 5 days.

On a scale of 1-10 (1 least effect, 10 maximum effect):2

b) N-Acetylcysteine

-   -   2400 mg, divided in three doses;

Moderate reduction of duration of illness to an average of 4 days.

On a scale of 1-10 (1 least effect, 10 maximum effect):5

c) Glycyrrhinic acid

-   -   1500 mg, divided in three doses;

Considerable reduction in the duration of illness to an average of 2.5 days;

On a scale of 1-10 (1 least effect, 10 maximum effect):7

The average duration of illness with the treatment combination of all three of the above substances a), b), and c) in the majority of the cases the duration of the illness was shortened to 24 hours or less. Exactly said: 30 Adults (Men and women) had an improvement in symptoms (decreasing tiredness and maliase) already after 30 to 60 minutes after taking the first dose of combination of a), b), and c). 24 hours later, 85% of the patients were completely without symptoms and able to return to work. The maximum duration in a few cases lasted 5 days.

90% of the patients stayed healthy. 10% of the patients who did not follow the suggestions to avoid alcohol and to have a full nights sleep, showed new symptoms which however after taking the treatment again quickly subsided.

Furtheron, 20 children between the ages of 7 to 15 years old were treated with half of the doses from the combination of a) b) and c). The results were the same as by the adults. That is, after 30 to 60 minutes a significant improvement of the symptoms was seen and after 24 hours, most of the children were completely without signs of illness so that they could return to school the next day.

This surprising synergy of the combination of the above three substances a), b) and c) was not to be expected. It was known for some time that glycyrrhicinic acid had antiviral activity, but the incredible enhancement of activity with zinc and thiols that lead to an extraordinary increase in the elimination of symptoms was not discovered before the development of the combination therapy.

The preparation in the invention is not only useful for those ill, but of great use also for the economy in that the symptoms of diseases causing inability to work (colds, flu's) can be eliminated in a short period of time. Side effects in the short duration of therapy are not observed.

The following examples elucidate the invention further:

EXAMPLES

In all examples the application of the combined individual doses was 500 mg glycyrrhinic acid (or about 10 ml (a small tablespoon) succus liquiritiae depuratus solutus 1+1 from the company Dr. Hetterich GmbH & Co. KG, Fuerth, Bavaria), 50 mg Zinc (as an element in the form of zinc orotate) and 800 mg N-Acetylcysteine. Patients with high fevers (above 38.5° C.) were given paracetamol in addition to the treatment to decrease the fever. (Slight fevers did not require any special treatment)

Example 1

A 12 year old girl presented with low grade fever, lethargy, tiredness, mylagia, sore throat, and general malaise following an infection (Streptococcus negative.) She was treated with half of the doses of the above combination and she showed improvement within an hour. The application was repeated every 6 hours (except for the night). In 24 hours she showed a general improvement and no symptoms of any virus infection and was back in school.

Example 2

A 15 year old girl was presented with fever, runny nose, watering eyes, sore throat, (Streptococcus negative) and mild cough. She was treated with half of the doses of the above combination. After 30 minutes the child felt better, with less malaise and lethargy, the rest of the symptoms were milder. The treatment was repeated twice after 6 hours, respectively. In 24 hours she had no symptoms. She preferred not to attend school but to stay home and rest for one more day.

Example 3

A 16 year old boy presented with myalgie, fatigue, malaise, lethargy and tiredness and fever (low grade). He was treated half of the doses of the above combination. He showed improvement in 30 minutes with more energy and less lethargy. The treatment was repeated every 6 hours (except for the night). The entire symptoms were gone in 24 hours. The boy returned to school the next day.

Example 4

A 38 year old Woman, complained of fever, malaise, runny nose, myalgia, lethargy, weakness and tiredness. She was given the above combination dosage at 10 A.M.. Half an hour later she had less symptoms, her lethargy was gone, but the general malaise was still evident. She received two more treatments during the day and by the next morning she could resume her daily activities without hinderness. The symptoms were all gone.

Example 5

A 52 year old woman presented with flu-like symptoms of the upper rispiratory, fever, headache, myalgia, tiredness, malaise and lethargy. She was treated with the above dosage combination and slept most of the day. Her symptoms were almost completely reduced by the second day where to be on the safe side we resumed the treatment twice on the second day. Symptoms were completely gone after the second day.

Example 6

A 42 year old man presented with fever (low grade), malaise, myalgia, sniffles, light cough and sore throat. He complained of his flu symptoms and general weakness and tiredness. He was given the above single dose of combined substances at 2: P.M. and slept until evening when he received another single dose of combined substances. The next moring he felt better and wanted to go to work, however it was recommended he take another treatment for the morning and at noon to insure that he did not have a relapse. He returned to work the next day, feeling no more symptoms or illness of any sort.

Example 7

A 58 year old man presented with flu like symptoms including fever (low grade), malaise, tiredness, myalgia, headache and sore throat. He was given the above combination in single dose three times in the first day. After the first treatment in the morning his symptoms of tiredness and malaise were reduced in 30 minutes, he was however still weak and rested the entire day. The next day he was more than 80% better but remained home the entire mornig, returning to work in the afternoon.

Example 8

A 65 year old woman complained of upper rispiratory symptoms including runny nose, sore throat, malaise, low grade fever, and light cough. She was treated with the above combination in the morning and rapidly felt better after 1 hour. She was however still with a sore throat and myalgia. The treatment was repeated twice that day and once in the following morning. Her illness was gone after 36 hours. 

1. Application of a combination comprising Zinc substances, at least one of the orally taken thiol substances with at least one free thiol group or a group which sets a thiol free when metabolized in a mammal, as the only pure plant substance glycyrrhicinic acid or the substance from succus liquiritiae, for the production of a medication to fight acute or chronic viral infections.
 2. Application according to claim 1, characterized in that the components even in separate application units are arranged together inside of one package.
 3. Application according to claim 1, characterized in that two of the three components are combined in a single substance.
 4. Application according to claim 1, characterized in that all three components are together in a single combined substance.
 5. Application according to claim 1, characterized in that the combination of at least one free thiol group, or a group that is metabolized in mammals to a free thiol is out of N-acetylcysteine, Methionine, cysteine, allylcysteine, alpha lipoic acid, or sulfur.
 6. Application according to claim 1, characterized in that the glycyrrhicinic acid is in the form of succus liquiritiae.
 7. Application according to claim 1, characterized in that it further includes one or more pharmaceutical applied non active ingredients.
 8. Application according to claim 1, wherein the acute or chronic viral infections includes virus infections with corona virus, rhino virus, coxsackie virus, influenza A- and B-viruses, Herpes viruses, cytomegalo viruses, Hepatitis A- and B- and C-Viruses, Epstein-Barr-virus, and other colds or flu viruses.
 9. Application according to claim 1, characterized in that it applies to virus diseases and diseases of the upper respiratory tract.
 10. Application according to claim 1, characterized in that the glycyrrhinicic acid be applied in a daily doses of 750 mg to 2000 mg, that the zinc be applied in a daily doses from 50 mg to 150 mg (in relation to the element zinc only) and the combination of at least one free thiol group or a group that is metabolized to a free thiol in a mammal, in a daily doses from 600 mg to 2400 mg.
 11. Application according to claim 10, characterized in that the daily doses is divided into at least two single doses.
 12. Application according to claim 2, characterized in that the combination of at least one free thiol group, or a group that is metabolized in mammals to a free thiol is out of N-acetylcysteine, Methionine, cysteine, allylcysteine, alpha lipoic acid, or sulfur.
 13. Application according to claim 3, characterized in that the combination of at least one free thiol group, or a group that is metabolized in mammals to a free thiol is out of N-acetylcysteine, Methionine, cysteine, allylcysteine, alpha lipoic acid, or sulfur.
 14. Application according to claim 4, characterized in that the combination of at least one free thiol group, or a group that is metabolized in mammals to a free thiol is out of N-acetylcysteine, Methionine, cysteine, allylcysteine, alpha lipoic acid, or sulfur.
 15. Application according to claim 6, characterized in that it further includes one or more pharmaceutical applied non active ingredients.
 16. Application according to claim 7, wherein the acute or chronic viral infections includes virus infections with corona virus, rhino virus, coxsackie virus, influenza A- and B-viruses, Herpes viruses, cytomegalo viruses, Hepatitis A- and B- and C-Viruses, Epstein-Barr-virus, and other colds or flu viruses.
 17. Application according to claim 8, characterized in that it applies to virus diseases and diseases of the upper respiratory tract.
 18. Application according to claim 9, characterized in that the glycyrrhinicic acid be applied in a daily doses of 750 mg to 2000 mg, that the zinc be applied in a daily doses from 50 mg to 150 mg (in relation to the element zinc only) and the combination of at least one free thiol group or a group that is metabolized to a free thiol in a mammal, in a daily doses from 600 mg to 2400 mg. 